Department of Nephrology, School of Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Clinical Research Center for Kidney Diseases, Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, University of Electronic Science and Technology of China, Chengdu, China.
Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.
Ren Fail. 2021 Dec;43(1):1551-1560. doi: 10.1080/0886022X.2021.2003208.
Defined differently from apoptosis, necrosis, and autophagy, ferroptosis has been implicated in acute kidney injury (AKI) such as ischemia-reperfusion injury induced AKI, folic acid caused AKI and cisplatin induced AKI. However, whether ferroptosis is involved in LPS induced AKI could be remaining unclear and there is still a lack of therapies associated with ferroptosis in LPS induced AKI without side effects. This study aimed to elucidate the role of isoliquiritigenin (ISL) in ferroptosis of LPS-induced AKI. We used LPS to induce renal tubular injury, followed by treatment with ISL both and . Human renal tubular HK2 cells were pretreated with 50 μM or 100 μM ISL for 5 h before stimulation with 2 μg/mL LPS. Mice were administered a single dose of either 50 mg/kg ISL orally or 5 mg/kg ferroptosis inhibitor ferrostatin-1 intraperitoneally before 10 mg/kg LPS injection. We found that LPS could induce mitochondria injury of renal tubular presented as the shape of mitochondria appeared smaller than normal with increased membrane density and are faction or destruction of mitochondrial crista through scanning electron microscope. Ferrostatin-1 significantly protected mice against renal dysfunction and renal tubular damage in LPS-induced AKI. ISL inhibited Fe and lipid peroxidation accumulation in LPS-stimulated HK2 cells. It also increased the expression of GPX4 and xCT, reduced the expression of HMGB1 and NCOA4 then attenuated mitochondria injury in renal tubular following LPS stimulation. These results indicated the potential role of ISL against ferritinophagy-mediated ferroptosis in renal tubular following LPS stimulation.
铁死亡与细胞凋亡、细胞坏死不同，已被牵涉到急性肾损伤（AKI）中，如缺血再灌注损伤诱导的 AKI、叶酸诱导的 AKI 和顺铂诱导的 AKI。然而，铁死亡是否参与脂多糖（LPS）诱导的 AKI 尚不清楚，并且在 LPS 诱导的 AKI 中没有副作用的情况下，仍然缺乏与铁死亡相关的治疗方法。本研究旨在阐明甘草查尔酮 A（ISL）在 LPS 诱导的 AKI 中铁死亡中的作用。我们使用 LPS 诱导肾小管损伤，然后用 ISL 处理，浓度分别为和。在 2μg/ml LPS 刺激前，人肾小管 HK2 细胞用 50μM 或 100μM ISL 预处理 5 小时。在 10mg/kg LPS 注射前，小鼠口服给予 50mg/kg ISL 单次剂量或腹腔内给予 5mg/kg 铁死亡抑制剂 ferrostatin-1。我们发现 LPS 可诱导肾小管线粒体损伤，表现为线粒体的形状比正常情况下更小，膜密度增加，嵴断裂或破坏，通过扫描电子显微镜观察。Ferrostatin-1 显著保护 LPS 诱导 AKI 中的小鼠免受肾功能障碍和肾小管损伤。ISL 抑制 LPS 刺激的 HK2 细胞中铁和脂质过氧化产物的积累。它还增加了 GPX4 和 xCT 的表达，降低了 HMGB1 和 NCOA4 的表达，从而减轻 LPS 刺激后肾小管中的线粒体损伤。这些结果表明 ISL 在 LPS 刺激后铁蛋白介导的铁死亡中对肾小管具有潜在作用。
